Heavy chain diseases (HCD) are rare tumor diseases of a lymphoproliferative nature, in which the synthesis of defective immunoglobulins (with missing fragments of light chains) occurs. There are several variants of the disease – HCD-α, HCD-γ, HCD-µ and HCD- δ. Clinical manifestations are caused by damage to the lymphatic system and hematopoietic organs (enlargement of the liver, spleen, lymph nodes, diarrhea, edema, exhaustion, etc.). Diagnosis is based on complex immunopathochemical studies. Treatment is aimed at suppressing the tumor process with the help of polychemotherapy (cytostatics, corticosteroids according to the scheme).
General information
Heavy chain diseases are malignant neoplasms (paraproteinemic hemoblastoses) characterized by hypersecretion of heavy chain fragments and the complete absence of light chains of immunoglobulins of various classes, which leads to damage to the lymphatic and hematopoietic systems. There are diseases of γ (gamma), α (alpha), µ (mu) and exceptionally rarely – δ (delta) heavy chains.
The clinical picture of diseases of this group is similar to lymphomas. There are diseases of heavy chains mainly in adults aged 20-40 years, more often in residents of Mediterranean countries. In total, several hundred cases of this variant of paraproteinemic hemoblastosis have been recorded in the world, and 85% of them are patients with HCD-α. For the first time, heavy chain disease with the secretion of heavy chain fragments γ (gamma) was described by Franklin in 1963.
Causes
Risk factors for the development of diseases include various infectious diseases of the respiratory tract, intestinal infections, helminthiasis, autoimmune pathology (rheumatoid arthritis, Sjogren’s syndrome, autoimmune hemolytic anemia, etc.). Due to the onset of somatic mutations, plasma cells lose part of the structural genes responsible for the production of light chains of immunoglobulins, and begin hypersecretion of aberrant heavy chains. At the same time, pathologically altered heavy chains (there is a deletion of the CH1 site in their central part) cannot bind to light chains, and the synthesized immunoglobulins become defective, defective. An excessive number of heavy chains leads to their accumulation in such structural cellular elements as the endoplasmic reticulum and the Golgi apparatus, their damage and, ultimately, cell death.
Symptoms of heavy Chain diseases
The clinical symptoms of heavy chain diseases are similar to the characteristic manifestations of lymphatic tumors (damage to the lymph nodes, liver and spleen, bone marrow), having their own characteristics depending on the specific variant of the disease.
The disease of heavy gamma chains (Franklin) is more common in men aged 50-60 years, manifested by fever (body temperature rises to 38-39 degrees and remains at this level for a long time), general weakness, abdominal pain, difficulty swallowing, pronounced weight loss (exhaustion), frequent viral and bacterial infections. During physical examination, there is an increase in lymph nodes, liver, spleen, thyroid gland. HCD-γ progresses rapidly, and most patients die 5-6 years after the onset of the disease from infectious complications (acute pneumonia, sepsis).
Alpha chain disease (HCD-α) is the most common variant of heavy chain pathology, affecting mainly adults aged 20-40 years living in Mediterranean countries and suffering from various intestinal diseases. The abdominal form of HCD-α is manifested by malabsorption syndrome: impaired absorption of food with the development of severe prolonged diarrhea, edema, skin lesions, hair loss, exhaustion. Patients are often disturbed by abdominal pain, general weakness, and may have a transient fever. As a rule, the peripheral lymph nodes are not enlarged, the liver and spleen are of normal size. Very rarely there is a bronchopulmonary form of the disease of heavy alpha chains, manifested by lung damage and an increase in mediastinal lymph nodes.
Heavy chain disease µ (mu) is a rare disease observed in some patients with chronic lymphocytic leukemia. At the same time, the symptoms are nonspecific: the lymph nodes are not enlarged, hepatomegaly, periodic fever, signs of general intoxication may be noted.
Delta chain disease is extremely rare (isolated cases of the disease have been described), manifested by bone marrow damage with a clinical picture observed in myeloma (bone pain, pathological fractures, bleeding, thrombosis, anemia syndrome), the development of chronic renal failure.
Diagnosis of heavy chain diseases
Diagnosis of heavy chain diseases is based on the identification of clinical signs of lymphoproliferative disease (enlargement of regional lymph nodes, liver and spleen, intoxication syndrome) and laboratory and instrumental studies to confirm the diagnosis of a specific variant of BC and exclude other diseases of the lymphatic system and hematopoietic organs.
In a clinical blood test, anemia is detected, often – leukopenia due to a decrease in the number of granulocytes, the appearance of atypical lymphoid and plasma cells, thrombocytopenia. ESR is usually elevated. When examining the bone marrow, an increase in the content of plasmocytes (or lymphocytes) is noted.
The final diagnosis is established after an immunochemical analysis of serum proteins and the identification of structurally defective H-chains that are not associated with light chains. In this case, monoclonal immunoglobulins are detected, in which there is only a fragment of a heavy chain. The number of normal immunoglobulins of various classes is reduced. Depending on the specific variant of heavy chain disease, alpha, gamma or mu chains can be detected during high–precision analysis – immunofixation of paraprotein. With BTC-α, fragments of alpha chains can be found not only in the blood and urine of patients, but also in the mucous membrane of the small intestine, as well as in the saliva of patients. In some cases, immunocytochemical diagnostics does not allow to establish a correct diagnosis due to the absence of pathological proteins in the blood serum at the time of examination.
Differential diagnosis of heavy chain diseases is carried out with lymphoblastic lymphomas, acute and chronic leukemias, autoimmune hemolytic anemia, immunodeficiency disorders of various etiologies, autoimmune diseases, malignant neoplasms. In the process of diagnosis, consultations are held with a hematologist, oncologist, allergist-immunologist, infectious disease specialist and other specialists, endoscopic examination of the stomach and duodenum, colon, respiratory tract is performed, if necessary, computed tomography of the chest, intestines, pelvis, ultrasound of the abdominal cavity and thyroid gland, as well as other studies.
Treatment
Currently, there are no effective means of treating diseases of heavy chains. According to the indications, combined chemotherapy can be performed, used for chronic lymphocytic leukemia and malignant non-Hodgkin’s lymphomas (administration of cyclophosphamide, doxorubicin, prednisone and other drugs in accordance with the selected treatment protocol). Sometimes a good, but short-term positive therapeutic effect is recorded with local irradiation of the spleen and lymph nodes.
In alpha-heavy chain disease, in some cases, it is possible to achieve good results when using long-term antibacterial therapy with penicillin and tetracycline drugs, as well as metronidazole for 6-9 months during the exacerbation period. With the same form of the disease, radiation therapy is sometimes prescribed in combination with the intake of glucocorticosteroid hormones.
The prognosis for heavy chain diseases is mostly unfavorable, therapeutic measures can ensure the achievement of temporary remission within 0.5-1 year.
